The long term goal of the proposed work is to characterize at high resolution the structure and chemistry of circuits in the mammalian brain that underlie the basic drives that keep individual animals alive and assure perpetuation of the species associated with hunger and thirst, defensive behavior, reproductive behavior, and the sleep/wake cycle. Previous neuroanatomical work has clarified the input/output relationships and neurotransmitters of medial hypothalamic subsystems subserving each of these functions, and shown that they project topographically to the hypothalamic lateral zone (LHZ). Functional evidence suggests that the LHZ plays an important role in positive reinforcement, behavioral arousal, and various aspects of motivated behavior, although the topographic organization of its neural inputs and axonal projections is very poorly understood. The proposed work is based on the hypothesis that the LHZ is differentiated such that particular regions are components of a specific anatomical/functional subsystem, other regions serve to link multiple subsystems, and yet others play a general or nonspecific, modulatory role in motivated behavior. Two specific aims, which are based on the use of experimental neuroanatomical methods in the rat, are designed to explore this hypothesis. (1) A systematic computer graphics may of LHZ differentiation into regions based on in situ hybridization patterns of neurotransmitter-related mRNA expression will be generated. And (2) the basic input/output relationships of these regions vis-a-vis instinctive behavior subsystems as well as other functional systems of the cerebral hemispheres and brainstem will e determined using combined axonal transport/histochemical methods. This analytical/synthetic approach is designed to provide a structural framework for the rational design of functional experiments, as well as provide new insights into, and eventually treatments for, diseases that involve forebrain neural systems controlling eating, drinking, aggression and defense, reproduction, the sleep-wake cycle, and presumably mood disorders as well.